Prostate cancer is the second leading cause of cancer mortality in American men. Whereas localized prostate cancer is highly treatable, metastasized prostate cancer has a 5-year survival rate of 33%. The long term goal of our research is to develop targeted, combination gene and drug delivery nanocarriers for treatment of metastatic prostate cancers. The objectives of this study are to 1) design and synthesize polymeric nanocarriers for simultaneous delivery of a small-molecule anti-cancer prodrug of geldanamycin and a gene encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 2) develop a HER2-targeted PEG- based shield that will localize carriers in tumor cells and release from the nanocarrier intracellularly to allow DNA delivery to the nucleus, and 3) determine the pharmacokinetics and disposition of these nanocarriers in rodent models of prostate cancer. Our rational is combination of drug and DNA delivery in a single carrier will maximize therapeutic benefit by utilizing the known synergy of TRAIL and geldanamycin, and by ensuring delivery of both to a tumor cells. The addition of an endosome pH triggered-release shield and HER2/neu targeting/internalization peptide will maximize tumor delivery and internalization, while minimizing toxicity to non- target tissues. Finally, these agents have little or no toxicity to normal tissues, limiting the possible side-effects and maximizing the therapeutic window. Project Narrative: This study is an innovative approach to improving human health by developing a HER2 targeted therapy for treating metastatic prostate cancer with a combination of gene and drug therapy. We will use a nanoscopic drug/gene carrier that targets only metastatic prostate cancer cells. If successful, this will provide a new platform for building treatments for HER2+ prostate cancers, an aggressive phenotype present in >80% of highly metastatic hormone refractory prostate tumors.